(571i) Role of Viscoelastic Properties in Predicting the Density of Pharmaceutical Compacts

Roller compaction process, which is gaining popularity as a dry granulation method is currently scaled up based on trial and error. Hence, it is necessary to gain a mechanistic understanding of the process in order to establish a better control on the compact final properties. Roller compactor performance is known to be a function of both the processing parameters (roll pressure, speed) and the material properties of the powder feed (particle size distribution, mixture composition, inter-particle friction) (1, 2). In addition, Microcrystalline Cellulose (MCC) has been reported to exhibit strong time dependent behavior and to have mechanical properties influenced by the interstitial air (3). The contact area between two particles is an important property in wet and dry granulation, that influences the final granule properties. Due to compaction, there is an increase in the contact area between two particles which is also concomitant to an increase in tensile strength and density. The overall objective of this research is to predict roller/uniaxial compact density as a function of known process conditions and material properties. The primary objective of this research was to explore the role of viscoelastic contact area of MCC and acetaminophen (APAP) mixtures to model roller/uniaxial compact density as a function of known process and material properties. The secondary objective was to evaluate Uniaxial compaction, which uses much less material, to simulate roller compaction. Powders used for experiments were composed of 0, 25 and 50% APAP (rest MCC PH200). Magnesium stearate (0.5%) and Silicon Dioxide (0.2%) were used as lubricant and flow aide respectively. Moisture content of each drug composition corresponded to 40 and 70% RH. Roller compaction of the powders was performed using an Alexanderwerk® roller compactor at roll speeds of 8, 10 and 12 rpm and roll pressures of 7.5, 10 and 12 MPa. The powders were compressed in a Uniaxial testing machine at a punch velocities of 0.5, 10, 25 mm/min and final pressures of 1000, 2000 and 3000 lbf. The stress relaxation of the uniaxial compact so formed was measured for 3000 s. Roller compact relaxation properties for each composition and moisture content were obtained by interpolating the relaxation properties based on Uniaxial compaction. The uniaxial and roller compacts so formed were recompressed to get the compaction properties of the solid. The small deformation contact area was calculated using equation by Lum and Duncan-Hewitt (1999) by using the solid compaction and relaxation properties. Using the same compaction and relaxation properties, the large deformation contact area was calculated using Finite Element software (COMSOL). The stress relaxation response was found to fit well to Maxwell model with two Maxwell elements and a spring in parallel (R2>0.99). The compaction curves were modeled using an exponential model (R2>0.99). It was found that stress relaxation and compaction parameters depended on the APAP composition, moisture content and on final compaction pressure. For both uniaxial and roller compaction, the viscoelastic contact area and final compact densities (roller and uniaxial) was found to increase with increasing pressure, decreasing APAP and increasing particle size. Pressure was found to have the maximum influence on contact area and density. Although density and contact area increased with pressure, the rate of increase decreased at higher pressures indicating reaching an asymptotic density, which is the true density of the powder. Power law models were found to describe the dependence of compact densities on the viscoelastic contact area (R2>0.99). Uniaxial compaction was found to be a satisfactory tool to predict roller compact densities.

References: 1. Bindhumadhavan, G., Seville, J. P. K. et al. (2005). Roll compaction of pharmaceutical excipient: Experimental validation of rolling theory for granular solids. Chemical Engineering Science 60: 3891-3897. 2. Pietsch, W (1991). Size enlargement by agglomeration. John Wiley & sons, New York. 3. Abdel-Hadi, A. I., Zhunpanska, O. I., and Cristescu, N. D. (2002). Mechanical properties of microcrystalline cellulose Part 1. Experimental results. Mechanics of Materials. 34: 373-390. 4. Lum, S. K. and Duncan-Hewitt, W.C. (1999). Powder Densification. 1. Particle-Particle Basis for Incorporation of Viscoelastic Material Properties. Journal of Pharmaceutical Sciences 88(2): 261-276.